MOST CLOSELY HLA MATCHED ALLOGENEIC VIRUS SPECIFIC CYTOTOXIC T-LYMPHOCYTES (CTL)

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT When patients undergo a hemopoietic stem cell transplant (HSCT) from a donor who is the best possible match to treat blood cancers or other blood diseases they have a risk of infection until they can grow a new immune system from the donor. During this period they may develop serious viral infections with Epstein Barr virus (EBV), cytomegalovirus and adenovirus being three of the most common viruses that can cause problems. Investigators have previously shown that it is possible to grow up special T cells called virus-specific CTLs from the transplant donor that can prevent and treat these viral infections when they are given back to the patient. However it takes 2-3 months to grow these cells so it is not a practical option to grow virus-specific CTLs from the transplant donor for every patient that gets an infection with one of these viruses. In this study, investigators will see if an alternative approach is to make banks of virus-specific CTLs from normal donors that could be stored frozen and then made available to treat subjects post transplant if they developed one of these viral infections. Virus-specific CTL lines will be grown from normal donors and frozen. To make the CTL lines we first infect blood cells called monocytes with a specially produced adenovirus (a vector) that also carries part of the Cytomegalovirus (CMV) gene. This is a disabled virus that cannot reproduce itself once infection has occurred so it cannot spread. These infected monocytes then stimulate the T cells to respond to adenoviruses and CMV, and kill the cells infected with these viruses. We then give a second stimulation to the T cells, using cells which are also infected with EBV (which we will make from donor blood by infecting them with EBV in the laboratory) so that the cells now recognize three viruses CMV, EBV and Adenovirus. Once we have made sufficient numbers of T cells we will test them to make sure they kill cells infected with these viruses and freeze them. If a transplant patient gets an infection with one of these viruses, and the infection persists despite standard therapy, he or she would be eligible to receive a suitably matched CTL line. The primary objective is to determine if this strategy is feasible and safe. One risk is that because the T cells we make are not a complete genetic (HLA) match for the recipient, they might attack the subject and cause a condition called graft versus host disease (GVHD). We will closely monitor for this complication. Secondary objectives are to determine the effects of the T cell infusion on the virus infection and to see if the recipients can stay immune to these viruses. We will also see how long the T cells survive.